The Importance of Diagnosing and Managing ICU Delirium *

Brenda T. Pun and E. Wesley Ely Chest 2007;132;624-636 DOI 10.1378/chest.06-1795 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/132/2/624.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2007by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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CHEST Recent Advances in Chest Medicine

The Importance of Diagnosing and Managing ICU Delirium*
Brenda T. Pun, RN, MSN; and E. Wesley Ely, MD, MPH, FCCP

ICU delirium represents a form of brain dysfunction that in many cohorts has been diagnosed in 60 to 85% of patients receiving mechanical ventilation. This organ dysfunction is grossly underrecognized because a majority of patients have hypoactive or quiet delirium characterized by negative symptoms (eg, inattention and a flat affect) not alarming the treating team. Hyperactive delirium, formerly called ICU psychosis, stands out because of symptoms such as agitation that may cause harm to self or staff, but is actually rare relative to hypoactive delirium and associated with a better prognosis. Delirium is often incorrectly thought to be transient and of little consequence. After adjusting for numerous covariates, delirium is a strong, independent predictor of prolonged length of stay, reintubation, higher mortality, and cost of care. Expanded work on patient safety and recommendations by professional societies have established the importance of delirium monitoring and recommended it as standard practice in ICUs all over the world. This evidence-based review for physicians, nurses, respiratory therapists, and pharmacists will outline why it is imperative that patients be routinely monitored for delirium. This review will discuss modifiable risk factors for delirium, such as metabolic disturbances or potent sedative and analgesic medications. Attention to mitigating risk factors, along with recommended pharmacologic approaches such as antipsychotic medications, may provide resolution of delirium in some patients, while others will persist with refractory brain dysfunction and long-term cognitive impairment following critical illness. (CHEST 2007; 132:624636)
Key words: aging; analgesia; cognitive impairment; critical care; delirium; encephalopathy; mechanical ventilation; protocols; respiratory failure; sedation Abbreviations: ASE Attention Screening Examination; CAM-ICU Confusion Assessment Method for the ICU; GABA aminobutyric acid; PAR Psychological Assessment Resources; RASS Richmond Agitation-Sedation Scale; SCCM Society of Critical Care Medicine; VUMC Vanderbilt University Medical Center; York-VA Veterans Affairs TN Valley Healthcare System-York Campus

n an executive published by I Association of summary Persons and the American Retired the Harvard Schools of Medicine and Public Health,1 delirium was considered one of six-leading causes of preventable injury in those 65 years old. Delirium is an acute confusional state defined by fluctuating mental status, inattention, and either disorganized thinking or an altered level of consciousness. This review will focus on
*From Vanderbilt University and the Tennessee Valley VA Geriatric Research Education and Clinical Center, Nashville, TN. Dr. Ely was supported by National Institutes of Health grants RO1 AG 072701A1 and AG 0102301A1 and the VA Merit Review Clinical Science Research and Development, the Measuring the Incidence and Determining Risk Factors for Neuropsychological Dysfunction in ICU Survivors study. Ms. Pun has received honoraria from Hospira, Inc. and Cardinal Health and serves as a consultant on research project for Hospira, Inc. Dr. Ely has received grant support and honoraria from Hospira, Pfizer, and Eli Lilly.
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advances in our understanding of delirium in critical care. This update is organized according to key questions that answer the why, what, and how of monitoring and managing delirium in critical illness. Why Should We Monitor for Delirium? For many years, the critical care community has focused on assessing, preventing, and reversing multiorgan dysfunction syndrome. However, the brain
Manuscript received July 19, 2006; revision accepted February 7, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Brenda T. Pun, RN, MSN, Center for Health Services Research, Vanderbilt Medical Center, Nashville, TN 372328300; e-mail: Brenda.Pun@vanderbilt.edu or www.ICUdelirium.org DOI: 10.1378/chest.06-1795
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has been subjected to relatively little formal study until recently. ICU patients, especially older persons, are among the most vulnerable hospitalized patients for the development of delirium. Studies27 have found that delirium develops in 20 to 50% of lowerseverity ICU patients or those not receiving mechanical ventilation, and in 60 to 80% of ICU patients receiving mechanical ventilation. Speaking further to the high prevalence of this organ dysfunction, a study8 enrolling only nondelirious patients had to exclude 80% of screened ICU patients due to delirium. This problem is neither benign nor self-limiting. ICU delirium is predictive of a threefold-higher reintubation rate and 10 additional days in the hospital.9 13 Additionally, ICU delirium is associated with higher ICU and in-hospital mortality.14 Even after controlling for preexisting comorbidities, severity of illness, coma, and the use of sedatives and analgesics, patients with ICU delirium have more than a threefold-increased risk of 6-month mortality compared to those without delirium (Fig 1).5,9 It is unknown if delirium is the cause of these outcomes or just a marker of an unidentified covariate. However, delirium risks are cumulative; for example, each additional day spent in delirium is associated with a 20% increased risk of prolonged hospitalization and a 10% increased risk of death.9 It is not surprising that delirium is independently associated with higher ICU costs ($22,346 vs $13,332, respectively) and hospital costs ($41,836 vs $27,106, re-

Figure 2. The impact of ICU delirium on costs: median ICU and hospital cost per patient. This histogram shows cost according to clinical categorization of ever delirium vs never delirium. Delirium was significantly and independently associated with increased ICU and hospital cost. Used with permission from Milbrandt et al.15

spectively) compared to those without delirium (Fig 2).15 Between 10% and 24% of patients experience persistent delirium that may be related to long-term cognitive impairment.3,16 While it is well known that patients with preexisting dementia are at risk for delirium (ie, delirium on dementia [Fig 3]),4,17,18 data are emerging that indicate delirium may lead to or even accelerate the acquisition of a dementia-like entity (ie, dementia following delirium).19 Approximately one third of ICU patients receiving mechanical ventilation have long-term cognitive impairment that has been doc-

Figure 1. Delirium in ICU patients is a risk factor for 6-month mortality. Kaplan-Meier curves of survival to 6 months among ICU patients. Patients with delirium in the ICU had a significantly higher mortality rate than patients without delirium. Used with permission from Ely et al.9 H.R. hazard ratio. Data in parenthesis indicate confidence interval.
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termining Risk Factors for Neuropsychological Dysfunction in ICU Survivors [or MIND ICU] study) and the National Institutes of Health (Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors [or BRAIN ICU] study). Given the poor outcomes associated with delirium, it can no longer be considered a benign problem that will clear when the patient is transferred from the ICU. Considering that 9 of 10 seriously ill patients declared they would rather die than survive with severe cognitive impairment,33 it is imperative that we begin to incorporate brain dysfunction into our prognostication schemes and discharge discussions. This form of organ dysfunction mandates attention and prioritization in the assessment and care of critically ill patients.

What Is Delirium?
Figure 3. Delirium on dementia: cumulative rates of delirium in ICU patients 70 years old with and without preexisting dementia. The graph depicts the cumulative rates of delirium stratified by dementia status in three separate periods: on hospital admission or baseline, by the end of the ICU period, and by the end of the post-ICU period up to 7 days. *Indicates statistical significance with p 0.05 for comparison of groups with and without dementia. Used with permission from McNicoll et al.4

umented up to 6 years after hospital discharge.10,19 24 Several studies19,25 have found a link between delirium and declining function. Rockwood et al26 studied cognitively intact geriatric medical patients over 3 years and found that patients with delirium had significantly higher dementia incidence than those without delirium (18.1% vs 5.6%). Dolan et al27 studied geriatric hip surgery patients and found that patients with delirium were twice as likely to have dementia diagnosed at 2 years. McCusker et al22 evaluated hospitalized geriatric patients and found that the 1-year mini-mental status examination scores of delirious patients were 5 points lower than patients without delirium. Last, Nelson et al28 found that the number of days spent in delirium or coma was significantly associated with an increased likelihood of discharge to a post-acute care facility as opposed to home and poorer functional status at 3 months and 6 months. This post-ICU long-term cognitive impairment involves memory, attention, and executive function problems (Fig 4) and leads to inability to return to work, impaired activities of daily living, increased risk of institutionalization, and decreased quality of life.29 32 The causes of this acquired cognitive impairment are being investigated in two large cohort studies funded by the Veterans Administration (Measuring the Incidence and De626

Delirium is defined by the Diagnostic and Statistical Manual of Mental Disorders34 as a disturbance of consciousness with inattention accompanied by a change in cognition or perceptual disturbance that develops over a short period (hours to days) and fluctuates over time. Although there are many hypothesized pathophysiologic mechanisms involved in the development of delirium, most are thought related to imbalances in neurotransmitters that modulate cognition, behavior, and mood. Varied terms have been used to describe the spectrum of acute cognitive impairment in critically ill patients, including ICU psychosis, ICU syndrome, acute confusional state, septic encephalopathy, and acute brain failure.20,35,36 The current consensus is to consistently use the unifying term delirium and subcategorize according to psychomotor symptoms (hyperactive, hypoactive, or mixed).37 Hyperactive delirium, in the past referred to as ICU psychosis, is rare in the pure form and is associated with a better overall prognosis.38 It is characterized by agitation, restlessness, attempting to remove catheters, and emotional lability.37,39 Hypoactive delirium, which is very common and often more deleterious for the patient in the long term,38 remains unrecognized in 66 to 84% of hospitalized patients.40,41 Amid a busy emergency department ICU shift, hypoactivity on the part of a patient does not seem like a problem and may be missed.42 44 This subtype is characterized by withdrawal, flat affect, apathy, lethargy, and decreased responsiveness.38,44,45 In terms of nosology, some refer to the hypoactive delirium as encephalopathy and restrict delirium to hyperactive patients. However, using separate terms proves difficult since patients may present with a mixed clinical picture or
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Figure 4. Cognitive impairment with the Rey-O Copy complex figure, a test of visuoconstruction in which the patient is asked to copy a complex geometric design while looking at the original. This figure shows the original Rey-O and the examples of two patients tested 3 months after hospital discharge (neither had any detectable baseline cognitive deficits). These images serve as a striking example of neuropsychological deficits that impair the visuospatial and executive abilities of patients long after ICU stay. Reproduced by special permission of the Publisher, Psychological Assessment Resources (PAR), Inc., 16204 North Florida Ave, Lutz, FL 33549, from the Rey Complex Figure Test and Recognition Trial by John E. Meyers, Kelly R. Meyers. Copyright 1989, 1992, 1995 by PAR, Inc. Further reproduction is prohibited without permission of PAR, Inc.

sequentially experience both subtypes. Peterson et al46 reported the rates of these subtypes in the ICU to be 1.6% hyperactive, 43.5% hypoactive, and 54.1% mixed (Fig 5). Many critical care providers believe hyperactive delirium is more common, but it is merely because these patients attract attention due to their immediate threat to self and others. These data underscore the importance of regular delirium monitoring because many delirium episodes will be invisible otherwise because of negative symptomatology. For quiet or hypoactive delirium, it is worth emphasizing that if you dont look, you wont find. How Do We Monitor for Delirium? The Society of Critical Care Medicine (SCCM) guidelines47 recommend monitoring delirium routinely in patients receiving mechanical ventilation. There are currently two validated tools for monitoring delirium in ICU patients: the Intensive Care Delirium Screening Checklist48 and the Confusion Assessment Method for the ICU (CAM-ICU).47 The Intensive Care Delirium Screening Checklist (Table 1) is an eight-item checklist with a sensitivity of 99% and specificity of 64% and interrater reliability of
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0.94.48 Each of the eight items is scored as absent or present (1 or 0, respectively) and summed. A score 4 indicates delirium. The CAM-ICU was adapted for use in nonverbal ICU patients from the original

Figure 5. Hypoactive and mixed delirium predominate in older and younger ICU patients: percentage of ICU patients with delirium by motoric subtypes (hyperactive, hypoactive, and mixed) stratified by age. Used with permission from Peterson et al.46
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Table 1ICU Delirium Screening Checklist*

Items Altered level of consciousness (if A or B, do not complete patient evaluation for the period) A: No response, score: none B: Response to intense and repeated simulation (loud voice and pain), score: none C: Response to mild or moderate stimulation, score: 1 D: Normal wakefulness, score: 0 E: Exaggerated response to normal stimulation, score: 1 Inattention (score: 0 to 1) Disorientation (score: 0 to 1) Hallucination-delusion-psychosis (score: 0 to 1) Psychomotor agitation or retardation (score: 0 to 1) Inappropriate speech or mood (score: 0 to 1) Sleep/wake cycle disturbance (score: 0 to 1) Symptom fluctuation (score: 0 to 1) Total (score: 0 to 8) *The scale is completed based on information collected from each entire 8-h shift or from the previous 24 h. Adapted from Bergeron et al,48 with the kind permission of Springer Science and Business Media. Obvious manifestation of an item 1 point; no manifestation of an item or no assessments possible 0 point.

Confusion Assessment Method,49 and includes a fourfeature assessment (Fig 6). Sensitivity and specificity values of the CAM-ICU are both 90%. The CAMICU is translated into over a dozen languages, easy to administer, takes on average 1 min to complete, and requires minimal training.2,50 CAM-ICU implementation projects within different types of hospitals have reported high compliance and accuracy51 (Fig 7). A complete description of the CAM-ICU and training materials including videos and translations can be found at www.ICUdelirium.org. Case Study The following case study demonstrates delirium assessment using the CAM-ICU. A brief description

of CAM-ICU features is needed to guide the reader in these examples. Feature 1 (change in mental status from baseline or fluctuating course) is assessed by comparing current mental status to the patients prehospital baseline or to the changes in the mental status over the previous 24 h. The patient has feature 1 if his or her mental status is altered compared to prehospital baseline, or is normal but has fluctuated in the past 24 h. Feature 2 (inattention) is assessed using the Attention Screening Examination (ASE). The ASE has two versions: auditory and visual. To conduct the auditory ASE (random letter A), the patient is asked to squeeze the testers hand when the letter A is said in a series of 10 letters. The visual version is only needed when a patient is unable to physically squeeze (eg, the patient is a quadriplegic or has severe critical illness myoneuropathy). For the visual ASE, the patient is shown 5 pictures and then asked to nod yes or no if he/she just saw the original 5 among 10 subsequent pictures. Inattention is deemed to present (ie, feature 2 positive) when the patient scores less than eight correct answers on either the auditory or visual ASE tests. Feature 3 (disorganized thinking) is assessed by asking four yes or no questions and having the patient follow a simple command to hold up two fingers with both hands (5 points total). If the patient gets three or fewer correct, he/she has disorganized thinking and is feature 3 positive. Feature 3 is technically only needed for alert and calm patients because they are feature 4 negative. Feature 4 (altered level of consciousness) is measured using a sedation scale such as the Richmond Agitation-Sedation Scale (RASS)52,53 [Table 2]. If a patient is anything but alert and calm (eg, RASS score other than 0), he/she is feature 4 positive. Delirium is present when features 1 and 2 and either 3 or 4 are positive (Fig 6, Table 3). Examination 1: Mr. A (day 1) is a 57-year-old patient admitted to the ICU in respiratory distress secondary to pneumonia and was placed on mechanical ventilation. Later that evening, he was found agitated, pulling at his gown, and attempting to get out of bed. At baseline, his family reported that he functioned at a high level and was an engineer. The nurse assessed him to be hyperalert with a RASS of 3. Attention was assessed by performing the ASE auditory (letter) test; he scored 6 of 10. According to this assessment, features 1, 2, and 4 were positive, and the patient was considered CAM-ICU positive with hyperactive delirium (Table 3). It was not necessary to assess for feature 3 in order to make the overall assessment.
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Figure 6. CAM-ICU. The diagnosis of delirium requires the presence of acute onset of changes or fluctuations in the course of mental status (feature 1) and inattention (feature 2), plus either disorganized thinking (feature 3) or an altered level of consciousness (feature 4). Used with permission from Ely et al.3 See www.ICUdelerium.org for step-by-step training materials and a short demonstration video.
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Figure 7. Large-scale implementation of sedation and delirium monitoring in the ICU: compliance and agreement within raters. These graphs are from two institutions: a university-based hospital (Vanderbilt University Medical Center [VUMC]) and community-based Veterans Affairs hospital (Veterans Affairs TN Valley Healthcare System-York Campus, Nashville, TN). Top, A: compliance with the two scales over time. Bottom, B: agreement between bedside medical ICU nurses and expert reference standard raters using the two tools over time. The baseline values noted on the X-axis were obtained during a preimplementation phase to allow comparison with data obtained on subsequent months following educational in-services and hands-on feedback geared to improve the quality of bedside nurses performance. Used with permission from Pun et al.51

Examination 2: Mr. A (same patient, day 2) was administered lorazepam twice during the night. The following day, his nurse assessed him and found that he opened his eyes to a verbal stimulus with suswww.chestjournal.org

tained eye contact for 10 s (ie, RASS score 1). He scored only 3 of 10 correct responses on the ASE auditory (letter) test. As on the previous day, features 1, 2, and 4 were positive, yet this time he was in
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Table 2The RASS*

Scale 4 3 2 1 0 1 2 3 4 5 Definitions Combative Very agitated Agitated Restless Alert and calm Drowsy Light sedation Moderate sedation Deep sedation Not arousable Description Combative, violent, immediate danger to staff Pulls or removes tubes or catheters; aggressive Frequent nonpurposeful movement, fights ventilator Anxious and apprehensive, but movements not aggressive or vigorous Not fully alert but has eye opening to voice and sustained eye contact ( 10 s) Briefly awakens to voice with eye opening and eye contact ( 10 s) Movement or eye opening to voice (but no eye contact) No response to voice, but movement or eye opening to physical stimulation No response to voice or physical stimulation

*Adapted from Sessler et al52 and Ely et al.53

hypoactive (quiet) delirium (Table 3). Although not necessary, the nurse assessed for feature 3. The patient answered two of the four simple yes or no questions incorrectly and was unable to follow the hold up two fingers command, thus displaying disorganized thinking (feature 3 positive). Examination 3: Mr. As (same patient, day 3) breathing improved, and he was successfully extubated. In the previous 24 h, he was assessed with RASS scores 3 and 2, but at the current time the patient was sitting calmly in his bed with his eyes open (ie, RASS score 0). He scored 10 of 10 on the ASE auditory (letter). This examination revealed that although feature 1 was positive due to fluctuating mental status, features 2 and 4 were not. This patient was no longer delirious (Table 3). Additional Pearls to Delirium Diagnosis: Someone who is attentive is not delirious. Inattention is pivotal in the diagnosis of delirium. Those meeting some features but not full criteria may have subsyndromal delirium, which is currently being investigated to establish its relationship to intermediate outcomes. Risk Factors/Etiology: What Are the Modifiable Risk Factors? One key strategy to prevent or diminish delirium is to identify and modify risk factors that lead to

delirium. Inouye et al54,55 developed a predictive model for delirium in the elderly non-ICU patients that classified risk factors into two categories: predisposing (baseline vulnerability) and precipitating (hospital related or iatrogenic).55 Numerous risk factors have been identified in non-ICU populations7,54 57 that fall into these categories, and ICU patients have an average of 11 4 (mean SD)10 of these reported risk factors (Table 4). Baseline risk factors that predispose patients to the development of delirium include dementia, apolipoprotein E4 phenotype, advanced age, comorbidity, and depression.4,36,55,56,58 Dubois et al59 found that preexisting hypertension and smoking (presumably due to relative hypoperfusion and nicotine withdrawal, respectively) were significantly associated with the development of ICU delirium. Similarly, Ouimet et al14 reported that hypertension and alcoholism were associated with ICU delirium. Pandharipande et al60 reported in medical ICU patients that increasing age and severity of illness scores were significant independent predictors of transitioning to delirium. Another investigation4 reported that preexisting dementia was a significant risk factor for delirium. Precipitating and iatrogenic risk factors represent areas of potential modification and thus intervention for delirium prevention and/or treatment. Precipitating factors include hypoxia, metabolic disturbances, electrolyte imbalances, with-

Table 3Summary of the Delirium Assessments (See Case Presentation)

Features Feature 1: does the patient have an acute change in mental status from baseline or fluctuation? Feature 2: is the patient inattentive? Feature 3: does the patient have disorganized thinking? Feature 4: does the patient have an altered level of consciousness? Overall CAM-ICU: is this patient delirious? Positive Day 1 Positive Day 2 Day 3 Positive (due to RASS fluctuation)

Positive No need to test Positive (agitated, RASS

Positive Positive 3) Positive (lethargic, RASS Positive (hypoactive delirium)

Negative No need to test 1) Negative (awake and alert, RASS Negative (not delirious) 0)

Positive (hyperactive delirium)

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Table 4 Risk Factors Associated With ICU Delirium

Preexisting risk factors (baseline vulnerability) Dementia Apolipoprotein E4 phenotype Chronic illness (including hypertension) Advanced age Depression Smoking Alcoholism Severity of illness on hospital admission Precipitating risk factors (hospital related or iatrogenic) Hypoxia Metabolic disturbances Electrolyte imbalances Sleep deficits* Congestive heart failure Sepsis Prolonged restraint use and immobility Withdrawal syndromes Acute infections (systemic and intracranial) Seizures Dehydration Hyperthermia Head trauma Vascular disorders Intracranial space-occupying lesions Medications Benzodiazepines Morphine/fentanyl Meperdine Propofol *Sleep deficits in ICU patients are hypothesized to cause delirium, although this area is currently in its infancy, and ongoing studies are forthcoming. Most consistently associated with non-ICU delirium.

Sleep deprivation or loss of circadian rhythm is another potentially modifiable risk factor. Critically ill patients have severe sleep deprivation and disruption of sleep architecture, averaging about 2 h of sleep every 24 h. The causes of sleep deprivation in the ICU consist of excessive noise and lighting, patient care activities, metabolic consequences of critical illness, mechanical ventilation, and sedative and analgesic medications.62 It is known that disturbance in duration and quality of sleep has detrimental effects on protein synthesis, cellular immunity, and energy expenditure resulting in cardiopulmonary and cognitive effects, yet the relationship between sleep and ICU delirium has not been well characterized.62,63 Studies are under way to understand how bedside care may be altered to reduce this organ dysfunction and improve immediate and longterm outcomes of ICU patients. How Should We Approach This Multifaceted Problem? Nonpharmacologic Prevention and Treatment In the non-ICU setting, risk factor modification has resulted in a 40% relative reduction in the development of delirium.64 Modifications include repeated reorientation of patients, repetitive provision of cognitively stimulating activities for the patients, nonpharmacologic sleep protocol, early mobilization, range-of-motion exercises, timely removal of catheters and physical restraints, use of eye glasses and magnifying lenses, hearing aids and earwax

drawal syndromes, acute infection (systemic and intracranial), seizures, dehydration, hyperthermia, head trauma, vascular disorders, immobilization, sleep deficiency, psychiatric medications, and intracranial space-occupying lesions.36,55,56 Medications are perhaps the most prevalent modifiable risk factor for ICU delirium. Sedatives and analgesics primarily work by altering neurotransmitter levels throughout the brain, which may be the primary mechanism in delirium development. For example, morphine and high-dose benzodiazepines (up to 15 mg) were also linked to delirium in unadjusted analysis.59 Ouimet et al14 reported that sedatives and analgesics increased risk of delirium threefold when used to induce coma. Pandharipande et al60 reported that lorazepam was an independent risk factor for daily transition to delirium (Fig 8), whereas fentanyl, morphine, and propofol trended toward delirium development but were not statistically significant. In a subsequent study61 of 100 surgical and trauma ICU patients, midazolam (odds ratio, 2.75; p 0.002) and fentanyl (odds ratio, 1.87; p 0.05) exposures were the strongest independent predictors of transitioning to delirium.
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Figure 8. Lorazepam is an independent risk factor for transitioning to delirium in the ICU. The probability of transitioning to delirium increased with the dose of lorazepam administered in the previous 24 h. This incremental risk was large at low doses and plateaued at approximately 20 mg/d. Used with permission from Pandharipande et al.60
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disimpaction, adequate hydration, use of scheduled pain protocol, and minimization of unnecessary noise/stimuli. Additionally, delirium-specific multidisciplinary education and nurse-led intervention programs have resulted in a decrease in the duration and severity of delirium.65,66 However, the success of such strategies will depend on the specific plan, the patient population, and compliance with implementation.66,67 For example, Lundstrom et al66 reported that patients on a ward where the staff received specific delirium education and bedside nursing care was reorganized to provide more patient care continuity experienced shorter duration of delirium, shorter hospital stay, and lower mortality.66 However, Cole et al67 found no difference in delirium rates in patients observed by an intervention nurse when compared to patients who received standard care. To date, nonpharmacologic protocolization-ofcare studies have focused on non-ICU populations, but they clearly need to be done in the ICU setting, where the margin for improvement is great due to higher baseline prevalence rates and longer durations of delirium. Currently, investigators are working to determine the most important modifiable risk factors to include in such trials. Pharmacologic Prevention and Treatment Coupled with a general lack of awareness of delirium, the absence of level I evidence has resulted in a great deal of indifference regarding ICU delirium and wide variations in pharmacologic treatment.68,69 Pharmacologic strategies center on either of the following: (1) optimizing the quantity and type of sedative and analgesic medications delivered to patients, or (2) instituting currently recommended medications such as antipsychotics. Benzodiazepines and propofol work primarily as -aminobutyric acid (GABA) agonists, an inhibitory neurotransmitter that affects wakefulness and is thought to be one of the major neurotransmitters involved in delirium etiology. The sedation and amnesia produced by GABA-mimetic drugs result in a decreased level of consciousness but impair slowwave sleep, which over time may predispose patients to delirium. While these medications have an important role in patient comfort, clinicians must strive to achieve balance in their administration. Daily interruption of sedatives and analgesics and protocolizing their delivery have both been shown to improve patient outcomes.70 73 The SCCM guidelines47 recommend that ICU teams set clinically appropriate target sedation levels using well-validated sedation scales and readdress these target levels daily to ensure medication titration to the desired clinical end point.
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Novel GABA-receptorsparing sedative agents may also reduce cognitive dysfunction seen in ICU patients. 2-Receptor agonists such as dexmedetomidine for short-term sedation in the ICU74 have stimulated research in this area. Dexmedetomidine inhibits the release of norepinephrine.74,75 Norepinephrine inhibition and the subsequent downstream affects on neurotransmitters such as histamine, orexin, GABA, and serotonin are similar to that seen in non-rapid eye movement sleep, and are responsible for the sedative property of this drug.76 Maldonado et al77 conducted a prospective, unblinded, randomized trial in which cardiac surgery patients sedated intraoperatively at sternal closure were randomized to either dexmedetomidine, propofol, or midazolam. The dexmedetomidine patients had dramatically lower incidence of delirium postoperatively (8%) as compared to those sedated with propofol (50%) or midazolam (50%). These findings should be confirmed in larger trials to determine whether different sedatives (eg, benzodiazepines vs dexmedetomidine) are related to a reduced prevalence and duration of delirium, and other important outcomes. There are currently no drugs with regulatory approval for the treatment of delirium. SCCM guidelines47,78 recommend haloperidol as the preferred agent for the treatment of delirium based on case series and anecdotal reports. Adverse effects associated with haloperidol include extrapyramidal symptoms, prolongation of the QTc, torsades de pointes, neuroleptic malignant syndrome, and akathisia. All patients receiving antipsychotic agents should be monitored for these.47 Few rigorous stud-

Table 5Summary Points on Management of Delirium in the ICU

Monitor delirium regularly in ICU patients using a valid, reliable tool (eg, The Delirium Screening Checklist or the CAM-ICU). Remember that the most is hypoactive and will be missed if not actively looked for (Fig 9). Discuss results of delirium assessments on all patients daily on interdisciplinary rounds. Identify patients with high number of risk factors for the development or persistence of delirium (eg, electrolyte imbalance, fever, addition of new medications; especially those with anticholinergic properties, uncontrolled pain, new onset of congestive heart failure or nosocomial infection, prolonged immobility and restrain use, sleep/wake cycle disturbance). Review sedation and analgesia therapy, and ensure that the patient is receiving the minimum doses needed to achieve comfort, realizing that narcotics are often used for the double effect of analgesia and sedation. Implement strategies for tight titration (eg, nurse-driven, patient-targeted sedation delivery with daily sedation vacations). Consider the benefit and risk profile of adding medications that might spare the use of sedatives and avoid respiratory suppression (eg, haloperidol or atypical antipsychotics).

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Figure 9. Delirium treatment algorithm. This empiric protocol, which is largely based on the current SCCM clinical practice guidelines,47 is the algorithm the authors use to treat delirium in their ICU. Some aspects are evidence based, while others represent expert opinion and are awaiting refinement through clinical trials. Such protocols need to be updated regularly with new data and also personalized at each medical center according to thought-leaders at that center. Specific recommendations about the choice of antipsychotics to treat delirium have not been described because there are limited data available regarding the preferential use of these medications in ICU patients. The nonpharmacologic interventions recommended in this protocol have shown beneficial results in non-ICU patients; however, extrapolation to the ICU populations is speculative at this time. H2 histamine type 2; max maximum; dx diagnosis; CHF congestive heart failure; CPAP continuous positive airway pressure; PEEP positive end-expiratory pressure; Sats oxygen saturation. This figure is available as a full landscape PDF file at http://icudelirium.org/delirium/training-pages/DeliriumProto%2001_30_07.pdf.

ies have been done to evaluate the efficacy of haloperidol or other antipsychotics in delirious patients.79 One report80 found that prophylactic treatment with low-dose haloperidol in elderly hip surgery patients reduced the duration and severity of delirium but not its incidence. A retrospective study81 found that patients who received haloperidol within 2 days of initiation of mechanical ventilation had a significantly lower hospital mortality rate when compared to patients who did not receive haloperidol. The atypical antipsychotics (eg, aripiprazole, olanzapine, quetiapine, and ziprasidone) may also be helpful in treating delirium. Their mechanisms of
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action are similar to haloperidol, but in addition to dopamine they affect a variety of neurotransmitters, including norepinephrine, serotonin, histamine, and acetylcholine.79,82 84 Skrobik et al83 reported that olanzapine and haloperidol had similar affects on delirium in medical and surgical ICU patients, but that olanzapine was associated with fewer adverse events. The results of this initial study83 should be confirmed in placebo-controlled trials. Kato et al85 reported a case study suggesting that genotyping may impact the treatment effect of antipsychotic drugs. A patient with a CYP2D6 poor metabolizer genotype had persistent delirium and severe extrapyramidal symptoms when treated with risperidone, which is
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metabolized by CYP2D6. The patient was switched to quetiapine (metabolized by CYP3A4), and the delirium cleared within 2 days without side effects. Considering individual-patient metabolic enzyme profiles may be a tool in guiding safer and more efficacious pharmacotherapy, but this is a controversial topic that is in its infancy. In early 2005, the Food and Drug Administration issued an alert86 that atypical antipsychotic medications are associated with mortality risk among elderly patients. This warning was supported by a large metaanalysis of demented outpatients who received antipsychotic medications for treatment of psychotic symptoms.87,88 Subsequently, Wang et al89 reported that haloperidol had an even higher mortality risk in non-ICU elderly patients than atypical antipsychotics. No placebo-controlled trials involving haloperidol and/or atypical antipsychotics have been done in the ICU. Milbrandt et al81 reported on a retrospective chart review in which haloperidol use in the ICU was associated with improved survival. The data above emphasize the need for more research in this area and underscore the importance of exercising caution when treating delirium.

rithm (Fig 9). This article has reviewed several non-ICU randomized trials with positive findings that, coupled with obvious issues such as correction of metabolic disturbances, avoiding overuse of psychoactive medications and prolonged restraints, and attempts at improving sleep, may offer an initial protocolized approach while awaiting results of ICUspecific investigations. As pointed out by Polderman and Smit,90 Inattention may be a basic feature of delirium, but it should not be a component of our attitude toward delirium in the ICU. References
1 Rothschild JM, Leape LL. The nature and extent of medical injury in older patients: research report. September 2000. AARP Public Policy Institute Issue Paper 2000-17. Available at: http://assets.aarp.org/rgcenter/health/2000_17_injury.pdf. Accessed March 25, 2007 2 Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001; 29:1370 1379 3 Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAMICU). JAMA 2001; 286:27032710 4 McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003; 51:591598 5 Lin SM, Liu CY, Wang CH, et al. The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med 2004; 32:2254 2259 6 Pandharipande P, Costabile S, Cotton B, et al. Prevalence of delirium in surgical ICU patients [abstract]. Crit Care Med 2005; 33:A45 7 Levkoff SE, Evans DA, Liptzin B, et al. Delirium: the occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med 1992; 152:334 340 8 Jones C, Griffiths RD, Slater T, et al. Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness. Intensive Care Med 2006; 32:923926 9 Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:17531762 10 Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27:18921900 11 Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003; 31:1226 1234 12 Thomason JW, Shintani A, Peterson JF, et al. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care 2005; 9:R375R381 13 Miller RR, Shintani A, Girard TD, et al. Delirium predicts extubation failure [abstract]. Proc Am Thorac Soc 2006; 3:42 14 Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 2007; 33:66 73 15 Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med 2004; 32:955962
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Conclusions Although delirium research in critical care is rapidly maturing, the weight of evidence already demonstrates that critical care clinicians cannot afford to ignore this form of organ dysfunction in our patients (Table 5). If we are to be comprehensive in our approach to monitoring and managing organ dysfunction, the brain should be a very active component of our daily discussion at the bedside in the ICU. This article has outlined key reasons to tip delirium onto the physicians radar screen and has supported each reason with evidence. Where evidence is emerging or not yet existent, we have also acknowledged this and offered timely solutions for the clinician. How might the physician begin this process of change in practice? First, one can start by making it clear that as a climate of patient safety is instilled in the institution, delirium will be a priority. Second, as recommended by the clinical practice guidelines, implement goal-directed sedation and delirium monitoring, frequent charting, and discussion on rounds as part of a daily ICU routine. Third, the physician should discuss preventive strategies that make sense for patients in the ICU setting. In addition to the specific recommendations for the management of pain, sedation, and delirium, the 2002 SCCM guidelines47 include a treatment algorithm. Additionally, we have included a sample delirium treatment algo634

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16 Marcantonio ER, Simon SE, Bergmann MA, et al. Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc 2003; 51:4 9 17 Voyer P, Cole MG, McCusker J, et al. Prevalence and symptoms of delirium superimposed on dementia. Clin Nurs Res 2006; 15:46 66 18 Fick DM, Kolanowski AM, Waller JL, et al. Delirium superimposed on dementia in a community-dwelling managed care population: a 3-year retrospective study of occurrence, costs, and utilization. J Gerontol A Biol Sci Med Sci 2005; 60:748 753 19 Jackson JC, Gordon SM, Hart RP, et al. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol Rev 2004; 14:8798 20 Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. Semin Respir Crit Care Med 2001; 22:115126 21 Hopkins RO, Weaver LK, Pope D, et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:50 56 22 McCusker J, Cole M, Dendukuri N, et al. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. Can Med Assoc J 2001; 165:575 583 23 Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj 2006; 20:263271 24 Rothenhausler HB, Ehrentraut S, Stoll C, et al. The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study. Gen Hosp Psychiatry 2001; 23:90 96 25 Hopkins RO, Jackson JC. Long-term neurocognitive function after critical illness. Chest 2006; 130:869 878 26 Rockwood K, Cosway S, Carver D, et al. The risk of dementia and death after delirium. Age Ageing 1999; 28:551556 27 Dolan MM, Hawkes WG, Zimmerman SI, et al. Delirium on hospital admission in aged hip fracture patients: prediction of mortality and 2-year functional outcomes. J Gerontol A Biol Sci Med Sci 2000; 55:M527M534 28 Nelson JE, Tandon N, Mercado AF, et al. Brain dysfunction: another burden for the chronically critically ill. Arch Intern Med 2006; 166:19931999 29 Aguero-Torres H, von Strauss E, Viitanen M, et al. Institutionalization in the elderly: the role of chronic diseases and dementia: cross-sectional and longitudinal data from a population-based study. J Clin Epidemiol 2001; 54:795 801 30 Strain LA, Blandford AA, Mitchell LA, et al. Cognitively impaired older adults: risk profiles for institutionalization. Int Psychogeriatr 2003; 15:351366 31 Chodosh J, Seeman TE, Keeler E, et al. Cognitive decline in high-functioning older persons is associated with an increased risk of hospitalization. J Am Geriatr Soc 2004; 52:1456 1462 32 Rockwood K, Brown M, Merry H, et al. Societal costs of vascular cognitive impairment in older adults. Stroke 2002; 33:16051609 33 Fried TR, Bradley EH, Towle VR, et al. Understanding the treatment preferences of seriously ill patients. N Engl J Med 2002; 346:10611066 34 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association, 2000 35 Granberg A, Engberg B, Lundberg D. Intensive care syndrome: a literature review. Intensive Crit Care Nurse 1996; 12:173182
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36 Webb JM, Carlton EF, Geeham DM. Delirium in the intensive care unit: are we helping the patient? Crit Care Nurs Q 2000; 22:47 60 37 Milisen K, Foreman MD, Godderis J, et al. Delirium in the hospitalized elderly: nursing assessment and management. Nurs Clin North Am 1998; 33:417 436 38 Meagher DJ, Trzepacz PT. Motoric subtypes of delirium. Semin Clin Neuropsychiatry 2000; 5:75 85 39 OKeeffe ST, Lavan JN. Clinical significance of delirium subtypes in older people. Age Ageing 1999; 28:115119 40 Marcantonio ER, Goldman L, Mangione CM, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994; 271:134 139 41 Inouye SK. The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients. Am J Med 1994; 97:278 288 42 Sanders AB. Missed delirium in older emergency department patients: a quality-of-care problem. Ann Emerg Med 2002; 39:338 341 43 Hustey FM, Meldon SW. The prevalence and documentation of impaired mental status in elderly emergency department patients. Ann Emerg Med 2002; 39:248 253 44 Meagher DJ, Hanlon DO, Mahony EO, et al. Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci 2000; 12:5156 45 Justic M. Does ICU psychosis really exist? Crit Care Nurse 2000; 20:28 37 46 Peterson JF, Pun BT, Dittus RS, et al. Delirium and its motoric subtypes: a study of 614 critically ill patients. J Am Geriatr Soc 2006; 54:479 484 47 Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119 141 48 Bergeron N, Dubois MJ, Dumont M, et al. Intensive care delirium screening checklist: evaluation of a new screening tool. Intensive Care Med 2001; 27:859 864 49 Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method: a new method for detection of delirium. Ann Intern Med 1990; 113:941948 50 Ely EW, Truman B, Manzi DJ, et al. Consciousness monitoring in ventilated patients: bispectral EEG monitors arousal not delirium. Intensive Care Med 2004; 30:15371543 51 Pun BT, Gordon SM, Peterson JF, et al. Large-scale implementation of sedation and delirium monitoring in the intensive care unit: a report from two medical centers. Crit Care Med 2005; 33:1199 1205 52 Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338 1344 53 Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003; 289:29832991 54 Inouye SK, Viscoli CM, Horwitz RI, et al. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:474 481 55 Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275:852 857 56 Francis J. Drug-induced delirium: diagnosis and treatment. CNS Drugs 1996; 5:103114 57 Francis J. Delirium in older patients. J Am Geriatr Soc 1992; 40:829 838
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58 Ely EW, Girard TD, Shintani AK, et al. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med 2006; 35:112117 59 Dubois MJ, Bergeron N, Dumont M, et al. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 2001; 27:12971304 60 Pandharipande PP, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:2126 61 Carson SS, Stocking C, Podsadecki T, et al. Effects of organizational change in the medical intensive care unit of a teaching hospital: a comparison of open and closed formats. JAMA 1996; 276:322328 62 Gabor JY, Cooper AB, Crombach SA, et al. Contribution of the intensive care unit environment to sleep disruption in mechanically ventilated patients and health subjects. Am J Respir Crit Care Med 2003; 167:708 715 63 Helton MC, Gordon SH, Nunnery SL. The correlation between sleep deprivation and the intensive care unit syndrome. Heart Lung 1980; 9:464 468 64 Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669 676 65 Milisen K, Foreman MD, Abraham IL, et al. A nurse-led interdisciplinary intervention program for delirium in elderly hip-fracture patients. J Am Geriatr Soc 2001; 49:523532 66 Lundstrom M, Edlund A, Karlsson S, et al. A multifactorial intervention program reduces the duration of delirium, length of hospitalization, and mortality in delirious patients. J Am Geriatr Soc 2005; 53:622 628 67 Cole MG, McCusker J, Bellavance F, et al. Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial. Can Med Assoc J 2002; 167:753759 68 Carnes M, Howell T, Rosenberg M, et al. Physicians vary in approaches to the clinical management of delirium. J Am Geriatr Soc 2003; 51:234 239 69 Ely EW, Stephens RK, Jackson JC, et al. Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals. Crit Care Med 2004; 32:106 112 70 Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541548 71 Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursingimplemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999; 27:2609 2615 72 Kress JP, Pohlman AS, OConnor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:14711477 73 Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interrup-

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The Importance of Diagnosing and Managing ICU Delirium* Brenda T. Pun and E. Wesley Ely Chest 2007;132; 624-636 DOI 10.1378/chest.06-1795 This information is current as of September 12, 2011
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/132/2/624.full.html References This article cites 87 articles, 28 of which can be accessed free at: http://chestjournal.chestpubs.org/content/132/2/624.full.html#ref-list-1 Cited Bys This article has been cited by 5 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/132/2/624.full.html#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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